Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD), but the mechanisms whereby mutant LRRK2 alters neuronal function and causes neurodegeneration remain poorly understood. In cell biological studies we directly link PD mutant forms of LRRK2 to activation of the FADD/caspase-8 signaling arm of the extrinsic cell death pathway. Notably, we find that 1) LRRK2, FADD and caspase-8 form a signaling complex, 2) LRRK2 PD mutations enhance its interaction with FADD, and 3) FADD and caspase-8 are required for the death of LRRK2-transfected primary neurons. The in vivo relevance of this complex is supported by our finding of caspase-8 activation in brain tissue from PD patients with LRRK2 mutations and PD mutant LRRK2 transgenic mice. In the current application, we propose to test whether signaling through FADD/caspase-8 is required for the nigrostriatal-related phenotypes seen in PD mutant LRRK2 transgenic mice, including reduced locomotion (L-dopa responsive), decreased striatal dopamine (DA) efflux, and axonal degeneration. In the first aim we will explore whether the time course and anatomic distribution of caspase-8 activation correlates with the behavioral and physiological phenotypes of LRRK2 transgenic mice. In the second and third aims will use Cre-transgenic and floxed FADD and caspase-8 mice together with the LRRK2 transgenic model to ask whether the loss of these signaling molecules reduces or prevents the behavioral, physiological or neurodegenerative phenotypes caused by PD mutant LRRK2. RELEVANCE (See instructions): Neurodegenerative illnesses such as Parkinson and Alzheimer disease are an increasingly prevalent problem in aging societies, yet no therapies exist that retard or prevent neurodegeneration. One reason for the lack of effective therapies is that the mechanisms underlying neuronal dysfunction and death are poorly understood. This project explores the deleterious effects of the most common Parkinson disease-causing gene in an effort to identify novel therapeutic targets for this disease.